Interferons (IFNs) are immunologically active proteins produced by mammalian cells following infectious or cytokine stimuli. As biologically active substances, IFNs have three broad modes of action: direct antiproliferative effects on tumor cells, direct antiviral effects inhibiting viral replication, and immunomodulatory (also referred to as immunostimulatory) effects on the mammalian immune system. Kalvakolanu, D. V., & Borden, B. C. Cancer Investigation, 14:25 (1996).
Interferons are generally divided into three species (IFN-α, IFN-β and IFN-γ) and two types according to their structural and functional characteristics. Type I IFNs (IFN-α and IFN-β) are produced following viral infection and have dosage dependent anti-tumor, anti-viral and immunomodulatory properties. Kopp, C. W. et al., Cancer Chemotherapy and Biological Response Modifiers, 15:226 (1994); Agrwala, S. S., & Kirkwood, M. J., Oncology, 51:129 (1994). Type II IFNs (IFN-γ) are produced by T lymphocytes following lymphokine stimulation. Kalvakolanu, V. D. & Borden, C. E., Cancer Investigation, 14:25 (1996). Type II IFNs have predominantly an immunomodulatory function with relatively less antiviral or antitumor activity.
Announced as a potential cure for cancer, IFNs have been used for treating several disease states, including chronic hepatitis C, multiple myeloma, multiple sclerosis, melanoma and CML. Kalvakolanu, V. D. & Borden, C. E., Cancer Invest., 14:25 (1996); Mughal, T. I. & Goodman, J. M., Ann. Onc., 6:537 (1995); Ucar, R. et al., Ann. Allergy, Asthma &Immun., 75:377 (1995); Sapiro, R. J. et al., Am. J. Nephr., 15:343 (1995); Sharara, A. I. et al., Ann. Int. Med., 125:658 (1996).
The current standard of care for human IFN cancer therapies utilizes antiproliferative IFN dosages. These dosages are maximum tolerable dosages at about 10–20 million U/m2 per day. Kirkwood, J. Clin. Oncol., 14:7–17 (1996). IFN treatments have had limited effectiveness against solid tumors. Moreover, antiproliferative IFN dosages can suppress multiple immune system parameters including NK lymphocytes. Maluish et al., J. Immun., 131:503 (1983).
Cancer therapy also includes surgical resection or debulking of a tumor mass. Surgical excision is not typically curative because surgery does not combat minimal residual disease. Minimal residual disease refers to cancer cells that have dissociated from a primary tumor either prior to surgery or during surgical resection. Current imaging techniques, such as CT scans and x-rays, are unable to detect these dissociated cancer cells. It is believed these dissociated cancer cells lead to primary tumor recurrence. Also, these undetected cells are the nidus of metastatic disease, which is considered the most significant component of cancer mortality.
To increase the cancer therapy success rate, chemical and immunological compounds are used in conjunction with surgical resection. Effective combined therapies are difficult to develop. One possible explanation for the lack of effective therapies is the phenomenon of transient postoperative immunological deficiencies observed for surgical patients. Slade et al., Surgery, 78: 363 (1975); Lee, Y. T., J. Surg. Onc., 9:425–430 (1977). This postoperative immunosuppression increases a patient's susceptibility to post-operative infections, tumor reoccurrence and metastasis. As a result, the medical community is still searching for effective cancer therapies.